Translational Insights into Estrogen Receptor alpha-Positive Luminal Breast Cance

描述（由申请人提供）：我们开发了一种新型雌激素受体α阳性（ER？+）小鼠模型STAT 1-/-小鼠中的乳腺癌，与ER？+表现出显著的相似性人类的乳腺癌。该模型的一个关键特征是来自这些小鼠的原发性肿瘤细胞>90%为ER阳性？和孕激素受体（PR），并在体外和体内显示雌激素生长依赖性。在基因表达谱的基础上，在STAT 1-/-小鼠中发展的乳腺肿瘤细胞显示出与人类管腔乳腺癌的非凡相似性。在发育上，该模型也忠实地再现了人类管腔型乳腺癌的自然史，包括进展为卵巢激素独立性的能力。因此，我们的模型填补了对最常见的人类乳腺癌形式的合适小鼠模型的长期需求。在这个U 01应用中，我们建议利用这个模型来了解更多关于管腔乳腺癌的起源和进展，并开发可以转化为人类的新疗法。我们组建了一个多学科、多机构的研究团队，利用最先进的技术实现以下四个具体目标。在具体目标1中，我们将完成ER？+的表征STAT 1-/-小鼠的（管腔）乳腺肿瘤，特别强调定义在这些肿瘤细胞中起作用的过度激活的JAK 2-STAT 3/5信号通路的作用，并鉴定ER？+乳腺肿瘤细胞表面，其负责失调的JAK 2-STAT 3/5信号传导或可用于将成像剂或治疗剂直接靶向肿瘤。在具体目标2中，我们将定义ER中发生的变化？STAT 1-/- ER？+中的JAK 2-STAT 3/5信号传导和基因表达研究了荷瘤小鼠卵巢切除术后长出的（腔）乳腺肿瘤，并探讨了这种进展的潜在机制。在具体目标3，我们将使用微型正电子发射断层扫描（microPET）成像，以确定功能上重要的变化，ER？ER？+的表达/功能、肿瘤细胞表面标志物的表达和细胞代谢/增殖在卵巢切除术之前和之后，在STAT 1-/-小鼠的（管腔）乳腺肿瘤中，并探索microPET是否可以用作治疗功效的替代标记物。最后，在具体目标4中，我们将开发新的组合肿瘤靶向疗法，以有效治疗携带自然产生和移植的小鼠ER？+的小鼠。（管腔）乳腺癌，希望将我们的发现转化为人类乳腺癌的新疗法

DESCRIPTION (provided by applicant): We have developed a novel mouse model of estrogen receptor-alpha positive (ER?+) mammary cancer in STAT1-/- mice that shows remarkable resemblance to ER?+ luminal breast cancer in humans. A key feature of this model is that primary tumor cells from these mice- are >90% positive for ER? and progesterone receptors (PR) and show estrogen growth dependency in vitro and in vivo. On the basis of gene expression profiling, the mammary tumor cells that develop in STAT1-/- mice show extraordinary similarity to human luminal breast cancers. Developmentally this model also faithfully recapitulates the natural history of human luminal breast cancer, including the capacity to progress to ovarian hormone independence. Thus, our model fills a long-standing need for a suitable mouse model of the most common form of human breast cancer. In this U0l application, we propose to capitalize on this model to learn more about the origins and progression of luminal breast cancers, and to develop novel therapies that can be translated to humans. We have assembled a multi-disciplinary, multi-institutional research team to pursue the following four Specific Aims using state-of-the-art technologies. In Specific Aim 1 we will complete the characterization of ER?+ (luminal) mammary tumors from STAT1-/- mice, placing special emphasis on defining the role(s) of the hyperactivated JAK2-STAT3/5 signaling pathway that is operative in these tumor cells, and in identifying differentially expressed proteins on ER?+ mammary tumor cell surfaces that are either responsible for the dysregulated JAK2-STAT3/5 signaling or might be used to target imaging agents or therapeutics directly to the tumor. In Specific Aim 2 we will define the changes that occur in ER? expression/signaling, JAK2-STAT3/5 signaling and gene expression in STAT1-/- ER?+ (luminal) mammary tumors that grow out following ovariectomy of tumor bearing mice, and explore the underlying mechanisms for this progression. In Specific Aim 3 we will use micro-positron emission tomography (microPET) imaging to identify functionally important changes in ER? expression/function, expression of tumor cell surface markers and cellular metabolism/proliferation of ER?+ (luminal) mammary tumors in STAT1-/- mice before and after ovariectomy, and explore whether microPET can be used as a surrogate marker of therapeutic efficacy. Finally, in Specific Aim 4 we will develop novel combinatorial tumor-targeted therapies to effectively treat mice bearing naturally arising and transplanted mouse ER?+ (luminal) mammary cancers with the hope of translating our findings into new treatments for human breast cancer